rs1114167806
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000251.3(MSH2):c.1457_1460delATGA(p.Asn486ThrfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000251.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Lynch syndrome 1 Pathogenic:3Other:1
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
The c.1457_1460delATGA pathogenic mutation, located in coding exon 9 of the MSH2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1457 to 1460, causing a translational frameshift with a predicted alternate stop codon (p.N486Tfs*10). This alteration has also been reported in multiple individuals with personal and/or family history consistent with Lynch syndrome and is described in the literature as a Chinese founder mutation (Chan TL et al, J. Natl. Cancer Inst. 1999 Jul; 91(14):1221-6; Yuen ST et al, Oncogene 2002 Oct; 21(49):7585-92; Chan TL et al, Am. J. Hum. Genet. 2004 May; 74(5):1035-42; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Cruz-Correa M et al. Fam Cancer, 2015 Sep;14:415-25; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27(5):795-800; Rossi BM et al. BMC Cancer 2017 Sep;17(1):623; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). Additionally, this alteration was identified in multiple patients with breast and/or ovarian cancer (Kwong A et al. J Mol Diagn, 2020 04;22:544-554). Of note, this alteration is also designated as c.1452_1455delAATG and c.1457del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant deletes 4 nucleotides in exon 9 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch Syndrome (PMID: 10413423, 12386821, 15042510, 25782445, 28874130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Carcinoma of colon Pathogenic:2
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The MSH2 p.Asn486ThrfsX10 variant was identified in 9 of 598 proband chromosomes (frequency: 0.015) from Asian individuals or families with colorectal cancer (Chan 1999, Chan 2004, Yuen 2002), and was not identified in 210 control chromosomes from healthy individuals (Chan 1999).The variant was also identified in dbSNP (ID: rs63750148), HGMD, “InSiGHT Colon Cancer Database” and the ClinVar database (classified as a pathogenic variant). The p.Asn486ThrfsX10 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 486 and leads to a premature stop codon 10 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. Two studies have suggested that p.Asn486ThrfsX10 variant is a founder mutation and is common in the southern Chinese population (Chan 2004, Yuen 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Lynch syndrome Pathogenic:1
Coding sequence variation introducing premature termination codon -
not provided Pathogenic:1
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25345868, 24710284, 15516845, 12386821, 24307375, 26787237, 15042510, 10413423, 32068069, 28874130, 28449805, 30730459, 31830689, 30521064, 28445943) -
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asn486Thrfs*10) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch Syndrome (PMID: 10413423, 28449805, 28874130). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. This variant is also known as c.1452_1455delAATG. ClinVar contains an entry for this variant (Variation ID: 90670). For these reasons, this variant has been classified as Pathogenic. -
Colon cancer Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at